Pancreatic cancer is an almost uniformly fatal illness, which is notoriously resistant to conventional chemotherapy. Indeed, the only chemotherapeutic agent approved by the FDA for use in this tumor -- gemcitabine -- has a response rate of approximately 5%, underscoring the need for innovative new approaches. Curcumin (diferuloyl methane) is a plant-derived compound that has been used extensively as a dietary ingredient. In vitro and animal model studies suggest that this compound has significant antitumor and chemotpreventive activity. In addition, pharmacologic doses of curcumin have been administered to patients in the phase I setting without significant side effects. Recently, we have demonstrated that curcumin has potent antiproliferative effects against all of five pancreatic cancer cell lines, with the 50% inhibitory concentration (IC/50) being < 5 mu/M in three of these lines. The antiproliferative effects were irreversible, and substantial apoptosis was noted. Of interest, NF-KappaB, which is constitutively active in pancreatic cancer cell lines, was downregulated after curcumin exposure. Levels of effectors including COX-2 and IL-8 were also decreased. On the basis of these results, we propose to do an exploratory clinical/translational trial of curcumin in patients with pancreatic cancer. Our primary objectives will include clinical goals such as determining the tolerance to, as well as response to, curcumin in patients with advanced pancreatic cancer. In addition, the biologic effect of curcumin on both tumor cells and peripheral blood mononuclear cells (the latter being used as a surrogate marker) will be assessed. In particular, the impact of curcumin on NF-KappaB activation, COX-2 and prostaglandin E2 levels, specific cytokine expression, and apoptosis will be evaluated. These studies should provide the foundation for the development of curcumin as an anticancer agent and may lead to a novel approach to the management of pancreatic cancer.